In FY2019, our first-in-human trial of PEN-866, a novel HSP90 inhibitor-SN38 drug conjugate which acts as an inhibitor of topoisomerase 1, continued enrolling patients in the phase 1a portion. The rationale for this study was based in part on preclinical work done in our lab demonstrating superior activity of PEN-866, as compared to other standard of care chemotherapy in models of pediatric sarcoma. Notably, the activity of PEN-866 was most durable in pediatric sarcoma models. Based on this, the ongoing clinical trial incorporates disease-specific expansion cohorts, including one for rhabdomyosarcoma and Ewing sarcoma, to include patients with these rare tumors. This trial is being conducted in collaboration with clinicians in the Developmental Therapeutics Branch. In the lab, we have continued to study PEN-866 in Ewing sarcoma and rhabdomyosarcoma, with a focus on identifying and overcoming potential mechanisms of resistance. In addition, we begun evaluating several novel topoisomerase 1 inhibitors (the indenoisoquinolines) in our pediatric sarcoma models, against the current standard of care topoisomerase agents for these diseases, in collaboration with Molecular Pharmacology Group in the Developmental Therapeutics Branch. Additionally, we have continued to study the mechanisms behind NAD depletion in cancer cells. Specifically, we are using inhibitors of the rate-limiting enzyme in the NAD salvage pathway, nicotinamide phosphoribosyltransferase (NAMPT), in preclinical models of pediatric solid tumors. We initially identified the exquisite sensitivity of Ewing sarcoma cells to these inhibitors as part of a collaboration with The National Center for Advancing Translational Science (NCATS). Based on this work, we have continued our preclinical studies to better understand role of NAD and NAMPT in Ewing sarcoma and in other pediatric solid tumors. To date, there have been no clinical studies of NAMPT inhibitors in any pediatric cancers. We are in the process of developing a pediatric trial for this patient population using the latest generation of these inhibitors. Lastly, we have identified several potential new agents and combinations of agents that impact the metabolic and DNA-repair machinery of cancer cells and are particularly effective in preclinical models of Ewing sarcoma. We are in the process of conducting mechanistic and in vivo studies to further describe the effects of these inhibitors. We expect the results from at least one of these studies to be published in FY2020.